It is no exaggeration to state that the story of
thalidomide is the story of the modern FDA. Thalidomide became
history’s most infamous drug in the late 1950s and early
1960s when it caused serious birth defects in thousands of
newborns. Congress, reacting to the tragedy, quickly passed
amendments to the Food, Drug, and Cosmetic Act which dramatically
toughened the FDA’s approach to new drugs. But the pendulum
has recently begun to swing the other way: aggravation with the
FDA’s time-consuming and expensive approval process for drugs
like thalidomide has led to expedited approval procedures and calls
for reform.

This paper is intended to document the over
thirty-year relationship between the FDA and thalidomide and to
describe in some detail the new uses for that drug. The
paper’s secondary goal is to demonstrate the power and
versatility of food and drug law online research; every source
cited herein, with the exception of the course materials, is
available to anyone with access to Westlaw and the World Wide
Web.[1]

The Original Uses Of Thalidomide

Thalidomide, one of the most notorious drugs in the
world, was first developed and sold in Europe in the 1950s as a
tranquilizer.[2] A West German company[3] brought it to market, and it was eventually sold
by fourteen companies in forty-six countries. Doctors in those
countries prescribed it to pregnant women as a relief for morning
sickness, not knowing of the drug’s horrible effect on their
offspring.[4] By 1961 or 1962, thalidomide’s
teratogenic[5] effect on gestating children was widely
recognized:[6] mothers taking the drug gave birth to children
with severe deformities,[7] including blindness, deafness, missing limbs, and
flipper-like appendages.[8] The exact number of victims is unknown; one
newspaper reported the total as 8,000 in 1985,[9] 12,000 in 1991,[10] and 8,000 again in 1993.[11] The exact number is not important, though; the
horror and outrage sparked by this disaster is.

Thalidomide was never approved by the FDA for use
in the United States, and therein lies one of the FDA’s
greatest success stories. In November of 1960, Dr. Francis Kelsey,
the FDA official charged with overseeing thalidomide’s New
Drug Application (NDA), was concerned that thalidomide might cause
neuropathy, a nerve disease, in some users.[12] She decided that the thalidomide NDA was
incomplete and refused to approve it.[13] This kept thalidomide tied up just long enough,
since in 1961 the drug’s effect on newborn children became
known.[14] In 1962, President Kennedy presented Dr. Kelsey
with a gold medal — the Distinguished Federal Civil Service
Award — for her efforts.[15]

This resounding success established the FDA’s
fundamental orientation on issues involving new drugs: better
extremely safe than sorry. Preventing “another
thalidomide” became the FDA’s number one priority; as
the current FDA Commissioner, Dr. David Kessler, put it,
“Back in the 1960s and 1970s, post-thalidomide, the
agency’s mission was to keep unsafe products off the
market.”[16] Perhaps due to the visibility of inappropriate
drug approvals, as opposed to the traditional invisibility
of inappropriate failures to approve new drugs,[17] some of the “protect the public at all
costs” attitude has carried though to the present day, with
defenders of the status quo “constantly” reminding
potential reformers of the thalidomide tragedy.[18]

Public outrage provided strong support for the
FDA’s new approach from the beginning. Books were written on
the topic,[19] and the word “thalidomide” entered
our lexicon as a harsh pejorative.[20] The drug even made a pop culture appearance in
Billy Joel’s 1989 hit “We Didn’t Start the
Fire.”[21] Recent studies of new uses for thalidomide have
suffered accordingly, due largely to “disbelief on the part
of many people — including physicians — that in light
of its catastrophic history, thalidomide would ever be offered to
anyone for any purpose.”[22]

Thalidomide And The 1962 Amendments

The change in the FDA’s attitude towards new
drugs was not the only result of the thalidomide tragedy. Just as
the elixir sulfanilamide poisonings of the 1930s prompted Congress
to pass the Food, Drug, and Cosmetic Act [hereinafter the Act] in
1938,[23] the horrors of the thalidomide babies pushed
Congress to enact the so-called “Kefauver
Amendments”[24] to the Act in 1962.[25]

Senator Kefauver’s motives were noble: he
intended the 1962 Amendments to “strengthen and broaden
existing laws in the drug field so as to bring about better, safer
medicine and to establish a more effective system of enforcement of
the drug laws.”[26] His bill was a complex piece of legislation,
but its most important provision — the one which would do the
most to bring about “better, safer medicine” —
was section nine, which authorized the FDA to deny an NDA if there
was not “substantial evidence” the drug would have its
claimed effect.[27] The original Food, Drug, and Cosmetic Act had
only required that new drugs be safe,[28] but Senator Kefauver argued that “the
marketing of a safe but ineffective drug may well be positively
injurious to the public health” since “[w]hen an
ineffective drug is prescribed, it is usually in the place of an
older but effective drug.”[29]

As several commentators have noted, there is some
irony in the fact that the thalidomide tragedy prompted Congress to
require a showing of efficacy and not just safety before FDA could
approve a new drug. Thalidomide itself was an effective drug; that
is, its tranquilizing qualities were never questioned, and it was
even favored over other sedatives since it didn’t produce the
usual “hangover effects.”[30] The problem with thalidomide, of course, was it
was unsafe for use by pregnant women, an issue which the
original FD&C Act, in theory, adequately addressed.[31] In fact, the introduction of the Kefauver
Amendments in Congress predated public knowledge of
thalidomide’s dangerousness.[32]

One provision of the 1962 Amendments did directly
address part of the existing law which could have — but
turned out not to have — been a problem in the FDA’s
consideration of thalidomide. The statute previously dictated that
an NDA would automatically be approved in sixty days unless it was
specifically disapproved or unless its effective date were
postponed up to a maximum of 180 days.[33] Congress, citing the need “to give the
physicians of the FDA adequate time to appraise the safety and
effectiveness of drugs,”[34] in section 6 of the bill extended the first
deadline to ninety days and abolished the second.[35] Current law provides that the Secretary of
Health and Human Services has 180 days from the filing of an NDA
application to approve the application, convince the applicant to
voluntarily delay it, or give the applicant an opportunity for a
hearing within the next four months, after which the
Secretary’s decision is due within three months.[36] In practice, this provision gave the FDA
tremendous leverage over drug manufacturers. A company which
refused to cooperate and voluntarily delay its NDA might find that
NDA denied, perhaps on the grounds that the company developed
insufficient information to justify approval, or its other drugs
delayed in the approval process. In the drug approval process, time
really is money, and a small company whose “burn rate”
is hovering around one-half million dollars per month cannot afford
to make an enemy of its regulator.

Dissatisfaction With The FDA: The New
Procedures

Despite the public support behind the 1962
Amendments, criticism soon began to tear at the edifice of the
Food, Drug, and Cosmetic Act. The critics attacked on three fronts.
First, as best articulated by Professor Peltzman, the 1962
Amendments resulted in the so-called “drug
lag.”[37] Professor Peltzman argued that the Amendments,
as of 1973, effectively prevented the development of twenty-five
new chemical compounds per year and resulted in a slowing pace of
drug development generally.[38] Unsurprisingly, mandating that the FDA give
proposed new drugs another layer of review slowed their approval.
Second, the efficacy requirement of Kefauver’s Amendments
resulted in increased drug prices. Higher approval hurdles
approximately doubled the research and development costs a company
could expect to incur, and the Amendments acted as a barrier to
market entry, weakening competition and allowing prices to rise in
the drug industry.[39] Third, the sick objected that whether or not to
use a drug is a personal choice, one that ought not be denied them
so long as a drug was safe: “Each person needs to decide for
themselves, in consultation with their physician ... which risks
they are willing to take.”[40]

These criticisms did not fall on a deaf ear at
Congress or at the FDA, and new, expedited and expanded procedures
were employed to remedy the perceived problems. The FDA established
a formal classification system for NDA and Investigational New
Drug, or IND, applications which categorized proposals based
primarily on their therapeutic potential.[41] The guidelines also took other factors into
account, such as whether the proposal concerned an orphan drug (see
below).[42] Then, in 1987, the FDA established a new
category, Type AA, for potential AIDS therapies; type AA drugs
receive the FDA’s highest priority in the drug review
process.[43]

The FDA has also set up programs under its
“compassionate use” framework to allow access to
unapproved drugs on a case-by-case basis for patients whose serious
illnesses have not responded to other therapies.[47] The FDA will invoke the primary compassionate
use mechanism, the Treatment IND, if the requested drug is
reasonably safe, if there are adequate protections of the patient
such as informed consent, and if the doctor administering the drug
keeps records as to its effect on the patient.[48] The FDA significantly expanded and revised the
Treatment IND program in 1987.[49] A related mechanism, the “parallel
track” policy, gives patients who are unable to participate
in clinical studies access to untested drugs.[50]

The FDA has also instituted expedited review and
accelerated approval for new drugs. Expedited review, begun in
1988, allows the FDA to assist manufacturers in setting up trials
and to waive the phase III study.[51] Under accelerated approval, begun in 1992, the
FDA may allow promising drugs to reach the market before their
complete effectiveness is demonstrated.[52]

The New Uses Of Thalidomide Under Expanded And
Accelerated FDA Procedures

After thalidomide’s fall from grace, few
people imagined that it would ever be prescribed again. The
surprising truth, however, is that thalidomide has been in nearly
constant use since scientists discovered its teratogenic effects
over thirty years ago.[53] This began after an Israeli doctor, treating a
patient with Hansen’s disease, or leprosy, administered
thalidomide in an attempt to sedate his patient.[54] The doctor found that not only did the
medication calm the patient, it also helped to fight the
disease.[55] Leprosy patients are the primary consumers of
thalidomide today,[56] and the drug is available through the U.S.
Public Health Service as part of a compassionate use
protocol.[57] Celgene, one of the corporations investigating
new uses for thalidomide, received Orphan Drug status for its use
of thalidomide as a leprosy treatment in 1993[58] and is expected to submit an NDA for that
indication in early 1997.[59]

Researchers, interested in thalidomide’s
unexplained success against leprosy, began to investigate the
drug.[60] They knew that leprosy is the result of a
bacterial infection and that some leprosy patients suffer from a
skin condition known as erythema nodosum leprosum, or ENL, if the
disease interferes with their immune system.[61] Studies indicated that thalidomide, a drug with
no antimicrobial effects (i.e. thalidomide couldn’t fight the
leprosy bacteria itself) was very effective in treating ENL, so
scientists reasoned that thalidomide acted directly on the immune
system.[62] Further experiments showed that thalidomide
reduced the immune system’s production and release of a
certain hormone-like protein — tumor necrosis factor, or TNF
— which acts as an intercellular messenger.[63] In normal concentrations TNF helps the body
fight pathogens, but certain chronic conditions cause the body to
overproduce it, leading to a number of unpleasant effects.[64] This was confirmed by one AIDS study in which
researchers administered TNF itself to patients and found it
significantly aggravated their symptoms.[65] Thalidomide’s ability to inhibit the
body’s use of TNF, like other TNF inhibitors, thus generally
doesn’t attack the disease directly; instead it
“attack[s] an underlying immune abnormality that occurs
because of the disease ... mak[ing] the disease easier to deal with
in a more direct fashion.”[66] In short, thalidomide prevents the immune
system of a person suffering from a chronic illness like leprosy
from actually harming the person.

Understanding the role of TNF in leprosy was not
the most significant finding of the researchers whose work is
described above. Leprosy is, after all, a rare,[67] though terrible, disease. Instead, the real
insight was the role thalidomide might play against other chronic
diseases in which the body’s TNF overproduction causes
serious and long-term harm: “Once the mechanism [of action]
in leprosy was established, we looked at other diseases associated
with high levels of TNF.”[68] This second-stage research has involved a large
number of afflictions. Diabetes research indicates that TNF may
have an impact on a diabetic’s insulin absorption and use, as
well as on glucose uptake, and researchers at Andrulis,[69] another company researching new uses for
thalidomide, have conducted a phase II trial of the drug.[70] Andrulis researchers are further investigating
whether the devastating neurological damage associated with
Alzheimer’s disease can be mitigated by thalidomide.[71] The company holds a patent for the use of
thalidomide in the treatment of Alzheimers and other neurological
disorders.[72] Celgene[73] is also investigating thalidomide’s
potential as a brain cancer therapy.[74] Still other researchers are looking at uses for
thalidomide in the treatment of bacterial meningitis, rheumatoid
arthritis, multiple sclerosis, tuberculosis, and a variety of other
diseases.[75]

At least judging by the amount of attention it has
garnered, however, the most exciting area of thalidomide research
involves HIV and AIDS. While ordinarily characterized as an
“immune deficiency,” a term which seems to indicate
that the body’s immune system is incapable of reacting to
disease, HIV also causes an “autoaggressive” reaction,
leading to the overproduction of TNF.[76] As with other diseases, too much TNF aggravates
the symptoms of AIDS, which include: prurigo nodularis, itchy bumps
on the skin;[77] diarrhea;[78] ulcers;[79] and cachexia, a severe weight loss condition
also known as “wasting.”[80] Thalidomide currently is being tested as a
therapy to all of those symptoms.

Most importantly, unlike thalidomide research for
other diseases, AIDS-related research has also uncovered evidence
that thalidomide may actually help retard the development of the
disease itself. Experiments have shown that TNF can both activate
latent HIV viruses[81] and enhance HIV replication.[82] It is thus possible that a TNF inhibitor such
as thalidomide may actually reduce a patient’s “viral
burden.”[83]

Perhaps unsurprisingly, given the constant pressure
applied by AIDS activists to the FDA,[84] AIDS-related indications of thalidomide have
been the beneficiary of the full range of expedited and expanded
FDA procedures. Celgene has received Orphan Drug status for
thalidomide’s use against both cachexia and mouth
ulcers,[85] and Andrulis won an Orphan Drug designation for
thalidomide’s use against a different type of mouth
sore.[86] Treatment INDs and parallel tracking are
available to sufferers of both ulcers and cachexia.[87] The FDA also has invoked its expedited review
by assisting the corporations in designing and implementing
clinical trials,[88] and by allowing phases II and III of the
required studies to be combined.[89] The devotion of the FDA’s time and
resources seems to have paid off: Celgene plans to apply for an NDA
for thalidomide’s use against cachexia early this
year.[90]

In the rush to test thalidomide as a treatment for
all of those diseases and symptoms, the drug’s most obvious
lesson — the potential for devastating birth defects —
has not been forgotten.[91] An FDA advisory committee held two days of
hearings on this subject in November, 1996,[92] where experts advised that the FDA consider
mandating two forms of birth controls for every pre-menopausal
non-sterile woman involved in any thalidomide study.[93] Some researchers, taking no chances, have
completely barred pregnant or nursing women from participating in
their studies.[94] This has not set well with some AIDS interest
groups, who argue that “[p]eople facing serious health
concerns deserve to make their own informed treatment
decisions.”[95] Given the horror of the previous generation of
thalidomide babies, however, they are unlikely to prevail.

Current Events

The interrelationship between thalidomide and the
evolution of the FDA did not stop at the FDA’s recent
procedural innovations. Arguments still swirl around the
controversial drug and the FDA’s handling of it and similar
drugs. But the attacks of the FDA’s critics are not new; in
fact, they are the same criticisms which led the FDA to implement
its new procedures only a few years ago.

The alleged “drug lag” is again at the
heart of the debate. Citing the now-familiar proposition that
“[p]atients can be harmed by delay in approving safe and
effective new medicines just as they can by the approval of unsafe
new medicines,”[96] reformers have accused the FDA of adhering to
its thalidomide-centered approach to drug approval.[97] One particularly harsh critic even maintains
that the FDA’s glacial review of beta-blockers resulted in
the death of hundreds of thousands by cardiac arrhythmia.[98] Critics also attack the drug review process as
being too costly, averaging nearly $350M per drug.[99] Finally, critics argue that a chronically and
terminally ill person’s decision to take a drug should rest
between that person and their doctor alone.[100] They reason that efficacy is irrelevant for a
new drug with the potential of treating patients with diseases like
AIDS, since with the drug sufferers might get better, but without
the drug they will surely die; so why not let them make their own
treatment decisions?

The FDA takes strong issue with these accusations.
Dr. Kessler put it bluntly: “The FDA is a world-wide leader
when it comes to reviewing and approving new drugs rapidly and
efficiently,” so “[i]t is time to put to rest the
incorrect perception that American patients generally suffer from a
so-called drug lag.”[101] The FDA published a report in 1995, entitled
“Timely Access to New Drugs in the 1990s: An International
Comparison,” which demonstrates that, on average, the FDA
approves drugs at least as fast as, if not faster than, its
counterparts in other countries.[102] The FDA also points out that AIDS-related
pharmaceuticals are approved particularly quickly: of the eight
antiretrovirals approved as of June 1996, the longest took six
months.[103] Finally, the FDA notes that 1996 was its best
year on record for drug approvals, as one hundred and thirty-one
new drugs were approved, a sixty percent increase over
1995.[104] Dr. Kessler, speaking to the Food and Drug
Law Institute, noted that the FDA approved forty-six New Molecular
Entities (NMEs[105] ) in fiscal year 1996, an approximate
one-hundred percent increase over recent years.[106] As for why it should still review drugs for
effectiveness even when patients suffer from fatal diseases, the
FDA responds that the critically ill need to be protected from
health care quacks and from substituting ineffective treatments for
effective ones.[107]

The current debate over the drug approval process
is complicated somewhat by the presence of the so-called
“buyer’s clubs,” organizations of activists who
break the law to make unapproved drugs available to the afflicted,
often those with AIDS.[108] These groups, who feel it is
“patronizing” for the FDA to tell AIDS-sufferers that
they “can’t take control of their own
therapy,”[109] have set up their own compassionate use
programs, participation in which generally requires a
doctor’s prescription and a patient’s informed
consent.[110] The FDA repeatedly warned the clubs to stop
supplying thalidomide,[111] but the clubs refused until a meeting between
them, the FDA, and Celgene, in which they agreed to stop supplying
the drug when the FDA made it widely available.[112]

Whatever advances the FDA’s expedited and
expanded procedures represent, AIDS patients have continued to
demand access to thalidomide.[113] Responding to such pressure, Congress has
jumped into the fray with two pieces of proposed legislation: The
Access to Medical Treatment Act [hereinafter the Access Act] and
the Food and Drug Administration Performance and Accountability Act
of 1995 [hereinafter the Performance Act].

The Access Act,[114] sponsored by Senate Minority Leader Tom
Daschle and cosponsored by at least sixteen other
senators,[115] would allow patients access to an unapproved
drug if there is no evidence that it is unsafe, if the manufacturer
is licensed, and if informed consent is obtained.[116] Essentially, the Access Act amounts to a
repeal of the efficacy provisions of the 1962 Amendments, at least
so far as certain drugs and patients are concerned. Senator
Daschle, testifying before the Senate Labor & Human Resources
Committee, said that “People should have the right to choose
from among a full range of medical treatment options —
particularly people who suffer from chronic and potentially fatal
conditions that do not respond to conventional
treatments.”[117] Jerold Mande, Commissioner Kessler’s
Executive Assistant, delivered the FDA’s response to the
Committee.[118] Mande pointed to the FDA’s recent
treatment of thalidomide as evidence of the FDA’s
“flexibility and open mindedness” and explained the
various ways in which the FDA is able to speed approval and access
to promising new drugs.[119] Mande also repeated the FDA’s position
on unapproved alternative therapies: allowing access to unapproved
drugs exposes vulnerable patients to unscrupulous snake-oil
salesmen and may encourage such patients to substitute ineffective
therapies for efficacious ones.[120] Senator Kassebaum, the Committee Chair,
stated the dilemma succinctly: “The fundamental question
before us today is how to achieve [the] balance between freedom of
choice, on the one hand, and a reasonable assurance of safety and
effectiveness, on the other.”[121]

The Performance Act, sponsored by Senator
Kassebaum, is an attempt to answer that question. Her bill would
“substantially shorten and make more efficient new product
development and FDA review times without compromising either safety
or effectiveness.”[122] The Performance Act would establish agency
performance standards, shorten new drug approval timetables, and
require the FDA to assist companies by helping to design test
trials and by telling them what standards will be used to evaluate
new drugs.[123] In short, Senator Kassebaum wants the best of
both words: fast and efficient yet full and complete drug review.
Dr. Kessler, testifying on the bill, said that while he shared her
goals, he did not believe that the FDA could meet the bill’s
requirements without additional resources.[124] Senator Kennedy, speaking on the floor of the
Senate, predicted that the Performance Act would place the FDA in
the grips of industry, leading to crises similar to Britain’s
mad-cow disease disaster.[125]

Conclusion

The exact resolution of the debate between FDA
review and patient autonomy is, at this stage, unclear. Regardless,
it appears certain that thalidomide’s unique status —
first as the impetus for the empowering of the FDA in 1962, now as
a major factor pushing for a stripping away much of that power
— will continue for the foreseeable future.

[1] In order to illustrate this dimension of the
paper, I will provide online “addresses” as part of the
citation form even where the Bluebook does not require them.

[6]Hartop , 311 F.2d at 265 n.5 (dissenting
opinion) (“It appears to be a matter of general knowledge [in
1962] that thalidomide, although effective as a sedative in human
beings, resulted in deformed offspring born to women who had taken
it during pregnancy.”).

[7] The vast majority of these children were born in
Britain, Germany, and Japan. SeeScourge ,
supra note 4, at 6.

[14]Id. There is, however, a dispute as to
whether Dr. Kelsey suspected thalidomide’s teratogenic
effects. See Steven B. Harris, The Right Lesson To Learn
From Thalidomide (1992) (visited Jan. 6, 1997)
<http://w3.aces.uiuc.edu/DLM/Liberty/Tales/Thalidomide.Html>.

[15] Peter van der Linden, The Medal From The
President (Nov. 11, 1994) (visited Jan. 7, 1997)
<http://www.best.com/~debunk/medical/dr_kelsey_thalidomide.html>
(citing The Insight Team, The Sunday Times of London, The Story
of Thalidomide (1979)). Dr. Kelsey still works at the FDA,
where she is currently the Director of the Division of Scientific
Investigations. Disease Associations: Thalidomide To Be Used For
AIDS Related Disorders Treatment , AIDS Weekly Plus, Nov. 25,
1996 [hereinafter Associations ], availablein
1996 WL 11522693.

[17]See Mary J. Ruwart, Death By
Regulation (visited Jan. 7, 1997)
<http://www.creative.net/~star/fda.htm> (“Former FDA
Commissioner Alexander Schmidt noted that ‘... rarely, if
ever, has Congress held a hearing to look into the failure of FDA
to approve a new entity; but it has held hundreds of hearings
alleging that the FDA has done something wrong by approving a
drug....’”); seealso Harris,
supra note 14 (“Even if the local doctor understands
the FDA’s role in preventing the patient from being properly
treated, ‘Stenosis of the Government’ is not a medical
diagnosis, and cannot be written on a death
certificate.”).

[105] NMEs are “products containing an active
substance that had never before been approved for marketing in any
form in the United States.” Id. FDA considers them a
particularly good symbol of its efficiency in getting new drugs to
patients. David Kessler, Remarks to the Food and Drug Law Institute
(1996), availablein
<http://www.fda.gov/opacom/kessler.html.